Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

Folkert W. Asselbergs; Yiran Guo; Erik P.A. Van Iperen; Suthesh Sivapalaratnam; Vinicius Tragante; Matthew B. Lanktree; Leslie A. Lange; Berta Almoguera; Yolande E. Appelman; John Barnard; Jens Baumert; Amber L. Beitelshees; Tushar R. Bhangale; Yii Der Ida Chen; Tom R. Gaunt; Yan Gong; Jemma C. Hopewell; Toby Johnson; Marcus E. Kleber; Taimour Y. Langaee; Mingyao Li; Yun R. Li; Kiang Liu; Caitrin W. McDonough; Matthijs F.L. Meijs; Rita P.S. Middelberg; Kiran Musunuru; Christopher P. Nelson; Jeffery R. O'Connell; Sandosh Padmanabhan; James S. Pankow; Nathan Pankratz; Suzanne Rafelt; Ramakrishnan Rajagopalan; Simon P.R. Romaine; Nicholas J. Schork; Jonathan Shaffer; Haiqing Shen; Erin N. Smith; Sam E. Tischfield; Peter J. Van Der Most; Jana V. Van Vliet-Ostaptchouk; Niek Verweij; Kelly A. Volcik; Li Zhang; Kent R. Bailey; Kristian M. Bailey; Florianne Bauer; Jolanda M.A. Boer; Peter S. Braund; Amber Burt; Paul R. Burton; Sarah G. Buxbaum; Wei Chen; Rhonda M. Cooper-Dehoff; L. Adrienne Cupples; Jonas S. Dejong; Christian Delles; David Duggan; Myriam Fornage; Clement E. Furlong; Nicole Glazer; John G. Gums; Claire Hastie; Michael V. Holmes; Thomas Illig; Susan A. Kirkland; Mika Kivimaki; Ronald Klein; Barbara E. Klein; Charles Kooperberg; Kandice Kottke-Marchant; Meena Kumari; Andrea Z. Lacroix; Laya Mallela; Gurunathan Murugesan; Jose Ordovas; Willem H. Ouwehand; Wendy S. Post; Richa Saxena; Hubert Scharnagl; Pamela J. Schreiner; Tina Shah; Denis C. Shields; Daichi Shimbo; Sathanur R. Srinivasan; Ronald P. Stolk; Daniel I. Swerdlow; Herman A. Taylor; Eric J. Topol; Elina Toskala; Joost L. Van Pelt; Jessica Van Setten; Salim Yusuf; John C. Whittaker; A. H. Zwinderman; Sonia S. Anand; Anthony J. Balmforth; Gerald S. Berenson; Connie R. Bezzina; Bernhard O. Boehm; Eric Boerwinkle; Juan P. Casas; Mark J. Caulfield; Robert Clarke; John M. Connell; Karen J. Cruickshanks; Karina W. Davidson; Ian N.M. Day; Paul I.W. De Bakker; Pieter A. Doevendans; Anna F. Dominiczak; Alistair S. Hall; Catharina A. Hartman; Christian Hengstenberg; Hans L. Hillege; Marten H. Hofker; Steve E. Humphries; Gail P. Jarvik; Julie A. Johnson; Bernhard M. Kaess; Sekar Kathiresan; Wolfgang Koenig; Debbie A. Lawlor; Winfried März; Olle Melander; Braxton D. Mitchell; Grant W. Montgomery; Patricia B. Munroe; Sarah S. Murray; Stephen J. Newhouse; N. Charlotte Onland-Moret; Neil Poulter; Bruce Psaty; Susan Redline; Stephen S. Rich; Jerome I. Rotter; Heribert Schunkert; Peter Sever; Alan R. Shuldiner; Roy L. Silverstein; Alice Stanton; Barbara Thorand; Mieke D. Trip; Michael Y. Tsai; Pim Van Der Harst; Ellen Van Der Schoot; Yvonne T. Van Der Schouw; W. M.Monique Verschuren; Hugh Watkins; Arthur A.M. Wilde; Bruce H.R. Wolffenbuttel; John B. Whitfield; G. Kees Hovingh; Christie M. Ballantyne; Cisca Wijmenga; Muredach P. Reilly; Nicholas G. Martin; James G. Wilson; Daniel J. Rader; Nilesh J. Samani; Alex P. Reiner; Robert A. Hegele; John J.P. Kastelein; Aroon D. Hingorani; Philippa J. Talmud; Hakon Hakonarson; Clara C. Elbers; Brendan J. Keating; Fotios Drenos

doi:10.1016/j.ajhg.2012.08.032

Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

Folkert W. Asselbergs, Yiran Guo, Erik P.A. Van Iperen, Suthesh Sivapalaratnam, Vinicius Tragante, Matthew B. Lanktree, Leslie A. Lange, Berta Almoguera, Yolande E. Appelman, John Barnard, Jens Baumert, Amber L. Beitelshees, Tushar R. Bhangale, Yii Der Ida Chen, Tom R. Gaunt, Yan Gong, Jemma C. Hopewell, Toby Johnson, Marcus E. Kleber, Taimour Y. LangaeeMingyao Li, Yun R. Li, Kiang Liu, Caitrin W. McDonough, Matthijs F.L. Meijs, Rita P.S. Middelberg, Kiran Musunuru, Christopher P. Nelson, Jeffery R. O'Connell, Sandosh Padmanabhan, James S. Pankow, Nathan Pankratz, Suzanne Rafelt, Ramakrishnan Rajagopalan, Simon P.R. Romaine, Nicholas J. Schork, Jonathan Shaffer, Haiqing Shen, Erin N. Smith, Sam E. Tischfield, Peter J. Van Der Most, Jana V. Van Vliet-Ostaptchouk, Niek Verweij, Kelly A. Volcik, Li Zhang, Kent R. Bailey, Kristian M. Bailey, Florianne Bauer, Jolanda M.A. Boer, Peter S. Braund, Amber Burt, Paul R. Burton, Sarah G. Buxbaum, Wei Chen, Rhonda M. Cooper-Dehoff, L. Adrienne Cupples, Jonas S. Dejong, Christian Delles, David Duggan, Myriam Fornage, Clement E. Furlong, Nicole Glazer, John G. Gums, Claire Hastie, Michael V. Holmes, Thomas Illig, Susan A. Kirkland, Mika Kivimaki, Ronald Klein, Barbara E. Klein, Charles Kooperberg, Kandice Kottke-Marchant, Meena Kumari, Andrea Z. Lacroix, Laya Mallela, Gurunathan Murugesan, Jose Ordovas, Willem H. Ouwehand, Wendy S. Post, Richa Saxena, Hubert Scharnagl, Pamela J. Schreiner, Tina Shah, Denis C. Shields, Daichi Shimbo, Sathanur R. Srinivasan, Ronald P. Stolk, Daniel I. Swerdlow, Herman A. Taylor, Eric J. Topol, Elina Toskala, Joost L. Van Pelt, Jessica Van Setten, Salim Yusuf, John C. Whittaker, A. H. Zwinderman, Sonia S. Anand, Anthony J. Balmforth, Gerald S. Berenson, Connie R. Bezzina, Bernhard O. Boehm, Eric Boerwinkle, Juan P. Casas, Mark J. Caulfield, Robert Clarke, John M. Connell, Karen J. Cruickshanks, Karina W. Davidson, Ian N.M. Day, Paul I.W. De Bakker, Pieter A. Doevendans, Anna F. Dominiczak, Alistair S. Hall, Catharina A. Hartman, Christian Hengstenberg, Hans L. Hillege, Marten H. Hofker, Steve E. Humphries, Gail P. Jarvik, Julie A. Johnson, Bernhard M. Kaess, Sekar Kathiresan, Wolfgang Koenig, Debbie A. Lawlor, Winfried März, Olle Melander, Braxton D. Mitchell, Grant W. Montgomery, Patricia B. Munroe, Sarah S. Murray, Stephen J. Newhouse, N. Charlotte Onland-Moret, Neil Poulter, Bruce Psaty, Susan Redline, Stephen S. Rich, Jerome I. Rotter, Heribert Schunkert, Peter Sever, Alan R. Shuldiner, Roy L. Silverstein, Alice Stanton, Barbara Thorand, Mieke D. Trip, Michael Y. Tsai, Pim Van Der Harst, Ellen Van Der Schoot, Yvonne T. Van Der Schouw, W. M.Monique Verschuren, Hugh Watkins, Arthur A.M. Wilde, Bruce H.R. Wolffenbuttel, John B. Whitfield, G. Kees Hovingh, Christie M. Ballantyne, Cisca Wijmenga, Muredach P. Reilly, Nicholas G. Martin, James G. Wilson, Daniel J. Rader, Nilesh J. Samani, Alex P. Reiner, Robert A. Hegele, John J.P. Kastelein, Aroon D. Hingorani, Philippa J. Talmud, Hakon Hakonarson, Clara C. Elbers, Brendan J. Keating, Fotios Drenos

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

177 Scopus citations

Abstract

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Original language	English (US)
Pages (from-to)	823-838
Number of pages	16
Journal	American journal of human genetics
Volume	91
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2012.08.032
State	Published - Nov 2 2012

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2012.08.032

Cite this

Asselbergs, F. W., Guo, Y., Van Iperen, E. P. A., Sivapalaratnam, S., Tragante, V., Lanktree, M. B., Lange, L. A., Almoguera, B., Appelman, Y. E., Barnard, J., Baumert, J., Beitelshees, A. L., Bhangale, T. R., Chen, Y. D. I., Gaunt, T. R., Gong, Y., Hopewell, J. C., Johnson, T., Kleber, M. E., ... Drenos, F. (2012). Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. American journal of human genetics, 91(5), 823-838. https://doi.org/10.1016/j.ajhg.2012.08.032

Asselbergs, FW, Guo, Y, Van Iperen, EPA, Sivapalaratnam, S, Tragante, V, Lanktree, MB, Lange, LA, Almoguera, B, Appelman, YE, Barnard, J, Baumert, J, Beitelshees, AL, Bhangale, TR, Chen, YDI, Gaunt, TR, Gong, Y, Hopewell, JC, Johnson, T, Kleber, ME, Langaee, TY, Li, M, Li, YR, Liu, K, McDonough, CW, Meijs, MFL, Middelberg, RPS, Musunuru, K, Nelson, CP, O'Connell, JR, Padmanabhan, S, Pankow, JS, Pankratz, N, Rafelt, S, Rajagopalan, R, Romaine, SPR, Schork, NJ, Shaffer, J, Shen, H, Smith, EN, Tischfield, SE, Van Der Most, PJ, Van Vliet-Ostaptchouk, JV, Verweij, N, Volcik, KA, Zhang, L, Bailey, KR, Bailey, KM, Bauer, F, Boer, JMA, Braund, PS, Burt, A, Burton, PR, Buxbaum, SG, Chen, W, Cooper-Dehoff, RM, Cupples, LA, Dejong, JS, Delles, C, Duggan, D, Fornage, M, Furlong, CE, Glazer, N, Gums, JG, Hastie, C, Holmes, MV, Illig, T, Kirkland, SA, Kivimaki, M, Klein, R, Klein, BE, Kooperberg, C, Kottke-Marchant, K, Kumari, M, Lacroix, AZ, Mallela, L, Murugesan, G, Ordovas, J, Ouwehand, WH, Post, WS, Saxena, R, Scharnagl, H, Schreiner, PJ, Shah, T, Shields, DC, Shimbo, D, Srinivasan, SR, Stolk, RP, Swerdlow, DI, Taylor, HA, Topol, EJ, Toskala, E, Van Pelt, JL, Van Setten, J, Yusuf, S, Whittaker, JC, Zwinderman, AH, Anand, SS, Balmforth, AJ, Berenson, GS, Bezzina, CR, Boehm, BO, Boerwinkle, E, Casas, JP, Caulfield, MJ, Clarke, R, Connell, JM, Cruickshanks, KJ, Davidson, KW, Day, INM, De Bakker, PIW, Doevendans, PA, Dominiczak, AF, Hall, AS, Hartman, CA, Hengstenberg, C, Hillege, HL, Hofker, MH, Humphries, SE, Jarvik, GP, Johnson, JA, Kaess, BM, Kathiresan, S, Koenig, W, Lawlor, DA, März, W, Melander, O, Mitchell, BD, Montgomery, GW, Munroe, PB, Murray, SS, Newhouse, SJ, Onland-Moret, NC, Poulter, N, Psaty, B, Redline, S, Rich, SS, Rotter, JI, Schunkert, H, Sever, P, Shuldiner, AR, Silverstein, RL, Stanton, A, Thorand, B, Trip, MD, Tsai, MY, Van Der Harst, P, Van Der Schoot, E, Van Der Schouw, YT, Verschuren, WMM, Watkins, H, Wilde, AAM, Wolffenbuttel, BHR, Whitfield, JB, Hovingh, GK, Ballantyne, CM, Wijmenga, C, Reilly, MP, Martin, NG, Wilson, JG, Rader, DJ, Samani, NJ, Reiner, AP, Hegele, RA, Kastelein, JJP, Hingorani, AD, Talmud, PJ, Hakonarson, H, Elbers, CC, Keating, BJ & Drenos, F 2012, 'Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci', American journal of human genetics, vol. 91, no. 5, pp. 823-838. https://doi.org/10.1016/j.ajhg.2012.08.032

@article{45eeb7ac06364d988eee3c136d287f69,

title = "Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci",

abstract = "Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.",

author = "Asselbergs, {Folkert W.} and Yiran Guo and {Van Iperen}, {Erik P.A.} and Suthesh Sivapalaratnam and Vinicius Tragante and Lanktree, {Matthew B.} and Lange, {Leslie A.} and Berta Almoguera and Appelman, {Yolande E.} and John Barnard and Jens Baumert and Beitelshees, {Amber L.} and Bhangale, {Tushar R.} and Chen, {Yii Der Ida} and Gaunt, {Tom R.} and Yan Gong and Hopewell, {Jemma C.} and Toby Johnson and Kleber, {Marcus E.} and Langaee, {Taimour Y.} and Mingyao Li and Li, {Yun R.} and Kiang Liu and McDonough, {Caitrin W.} and Meijs, {Matthijs F.L.} and Middelberg, {Rita P.S.} and Kiran Musunuru and Nelson, {Christopher P.} and O'Connell, {Jeffery R.} and Sandosh Padmanabhan and Pankow, {James S.} and Nathan Pankratz and Suzanne Rafelt and Ramakrishnan Rajagopalan and Romaine, {Simon P.R.} and Schork, {Nicholas J.} and Jonathan Shaffer and Haiqing Shen and Smith, {Erin N.} and Tischfield, {Sam E.} and {Van Der Most}, {Peter J.} and {Van Vliet-Ostaptchouk}, {Jana V.} and Niek Verweij and Volcik, {Kelly A.} and Li Zhang and Bailey, {Kent R.} and Bailey, {Kristian M.} and Florianne Bauer and Boer, {Jolanda M.A.} and Braund, {Peter S.} and Amber Burt and Burton, {Paul R.} and Buxbaum, {Sarah G.} and Wei Chen and Cooper-Dehoff, {Rhonda M.} and Cupples, {L. Adrienne} and Dejong, {Jonas S.} and Christian Delles and David Duggan and Myriam Fornage and Furlong, {Clement E.} and Nicole Glazer and Gums, {John G.} and Claire Hastie and Holmes, {Michael V.} and Thomas Illig and Kirkland, {Susan A.} and Mika Kivimaki and Ronald Klein and Klein, {Barbara E.} and Charles Kooperberg and Kandice Kottke-Marchant and Meena Kumari and Lacroix, {Andrea Z.} and Laya Mallela and Gurunathan Murugesan and Jose Ordovas and Ouwehand, {Willem H.} and Post, {Wendy S.} and Richa Saxena and Hubert Scharnagl and Schreiner, {Pamela J.} and Tina Shah and Shields, {Denis C.} and Daichi Shimbo and Srinivasan, {Sathanur R.} and Stolk, {Ronald P.} and Swerdlow, {Daniel I.} and Taylor, {Herman A.} and Topol, {Eric J.} and Elina Toskala and {Van Pelt}, {Joost L.} and {Van Setten}, Jessica and Salim Yusuf and Whittaker, {John C.} and Zwinderman, {A. H.} and Anand, {Sonia S.} and Balmforth, {Anthony J.} and Berenson, {Gerald S.} and Bezzina, {Connie R.} and Boehm, {Bernhard O.} and Eric Boerwinkle and Casas, {Juan P.} and Caulfield, {Mark J.} and Robert Clarke and Connell, {John M.} and Cruickshanks, {Karen J.} and Davidson, {Karina W.} and Day, {Ian N.M.} and {De Bakker}, {Paul I.W.} and Doevendans, {Pieter A.} and Dominiczak, {Anna F.} and Hall, {Alistair S.} and Hartman, {Catharina A.} and Christian Hengstenberg and Hillege, {Hans L.} and Hofker, {Marten H.} and Humphries, {Steve E.} and Jarvik, {Gail P.} and Johnson, {Julie A.} and Kaess, {Bernhard M.} and Sekar Kathiresan and Wolfgang Koenig and Lawlor, {Debbie A.} and Winfried M{\"a}rz and Olle Melander and Mitchell, {Braxton D.} and Montgomery, {Grant W.} and Munroe, {Patricia B.} and Murray, {Sarah S.} and Newhouse, {Stephen J.} and Onland-Moret, {N. Charlotte} and Neil Poulter and Bruce Psaty and Susan Redline and Rich, {Stephen S.} and Rotter, {Jerome I.} and Heribert Schunkert and Peter Sever and Shuldiner, {Alan R.} and Silverstein, {Roy L.} and Alice Stanton and Barbara Thorand and Trip, {Mieke D.} and Tsai, {Michael Y.} and {Van Der Harst}, Pim and {Van Der Schoot}, Ellen and {Van Der Schouw}, {Yvonne T.} and Verschuren, {W. M.Monique} and Hugh Watkins and Wilde, {Arthur A.M.} and Wolffenbuttel, {Bruce H.R.} and Whitfield, {John B.} and Hovingh, {G. Kees} and Ballantyne, {Christie M.} and Cisca Wijmenga and Reilly, {Muredach P.} and Martin, {Nicholas G.} and Wilson, {James G.} and Rader, {Daniel J.} and Samani, {Nilesh J.} and Reiner, {Alex P.} and Hegele, {Robert A.} and Kastelein, {John J.P.} and Hingorani, {Aroon D.} and Talmud, {Philippa J.} and Hakon Hakonarson and Elbers, {Clara C.} and Keating, {Brendan J.} and Fotios Drenos",

year = "2012",

month = nov,

day = "2",

doi = "10.1016/j.ajhg.2012.08.032",

language = "English (US)",

volume = "91",

pages = "823--838",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

AU - Asselbergs, Folkert W.

AU - Guo, Yiran

AU - Van Iperen, Erik P.A.

AU - Sivapalaratnam, Suthesh

AU - Tragante, Vinicius

AU - Lanktree, Matthew B.

AU - Lange, Leslie A.

AU - Almoguera, Berta

AU - Appelman, Yolande E.

AU - Barnard, John

AU - Baumert, Jens

AU - Beitelshees, Amber L.

AU - Bhangale, Tushar R.

AU - Chen, Yii Der Ida

AU - Gaunt, Tom R.

AU - Gong, Yan

AU - Hopewell, Jemma C.

AU - Johnson, Toby

AU - Kleber, Marcus E.

AU - Langaee, Taimour Y.

AU - Li, Mingyao

AU - Li, Yun R.

AU - Liu, Kiang

AU - McDonough, Caitrin W.

AU - Meijs, Matthijs F.L.

AU - Middelberg, Rita P.S.

AU - Musunuru, Kiran

AU - Nelson, Christopher P.

AU - O'Connell, Jeffery R.

AU - Padmanabhan, Sandosh

AU - Pankow, James S.

AU - Pankratz, Nathan

AU - Rafelt, Suzanne

AU - Rajagopalan, Ramakrishnan

AU - Romaine, Simon P.R.

AU - Schork, Nicholas J.

AU - Shaffer, Jonathan

AU - Shen, Haiqing

AU - Smith, Erin N.

AU - Tischfield, Sam E.

AU - Van Der Most, Peter J.

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Verweij, Niek

AU - Volcik, Kelly A.

AU - Zhang, Li

AU - Bailey, Kent R.

AU - Bailey, Kristian M.

AU - Bauer, Florianne

AU - Boer, Jolanda M.A.

AU - Braund, Peter S.

AU - Burt, Amber

AU - Burton, Paul R.

AU - Buxbaum, Sarah G.

AU - Chen, Wei

AU - Cooper-Dehoff, Rhonda M.

AU - Cupples, L. Adrienne

AU - Dejong, Jonas S.

AU - Delles, Christian

AU - Duggan, David

AU - Fornage, Myriam

AU - Furlong, Clement E.

AU - Glazer, Nicole

AU - Gums, John G.

AU - Hastie, Claire

AU - Holmes, Michael V.

AU - Illig, Thomas

AU - Kirkland, Susan A.

AU - Kivimaki, Mika

AU - Klein, Ronald

AU - Klein, Barbara E.

AU - Kooperberg, Charles

AU - Kottke-Marchant, Kandice

AU - Kumari, Meena

AU - Lacroix, Andrea Z.

AU - Mallela, Laya

AU - Murugesan, Gurunathan

AU - Ordovas, Jose

AU - Ouwehand, Willem H.

AU - Post, Wendy S.

AU - Saxena, Richa

AU - Scharnagl, Hubert

AU - Schreiner, Pamela J.

AU - Shah, Tina

AU - Shields, Denis C.

AU - Shimbo, Daichi

AU - Srinivasan, Sathanur R.

AU - Stolk, Ronald P.

AU - Swerdlow, Daniel I.

AU - Taylor, Herman A.

AU - Topol, Eric J.

AU - Toskala, Elina

AU - Van Pelt, Joost L.

AU - Van Setten, Jessica

AU - Yusuf, Salim

AU - Whittaker, John C.

AU - Zwinderman, A. H.

AU - Anand, Sonia S.

AU - Balmforth, Anthony J.

AU - Berenson, Gerald S.

AU - Bezzina, Connie R.

AU - Boehm, Bernhard O.

AU - Boerwinkle, Eric

AU - Casas, Juan P.

AU - Caulfield, Mark J.

AU - Clarke, Robert

AU - Connell, John M.

AU - Cruickshanks, Karen J.

AU - Davidson, Karina W.

AU - Day, Ian N.M.

AU - De Bakker, Paul I.W.

AU - Doevendans, Pieter A.

AU - Dominiczak, Anna F.

AU - Hall, Alistair S.

AU - Hartman, Catharina A.

AU - Hengstenberg, Christian

AU - Hillege, Hans L.

AU - Hofker, Marten H.

AU - Humphries, Steve E.

AU - Jarvik, Gail P.

AU - Johnson, Julie A.

AU - Kaess, Bernhard M.

AU - Kathiresan, Sekar

AU - Koenig, Wolfgang

AU - Lawlor, Debbie A.

AU - März, Winfried

AU - Melander, Olle

AU - Mitchell, Braxton D.

AU - Montgomery, Grant W.

AU - Munroe, Patricia B.

AU - Murray, Sarah S.

AU - Newhouse, Stephen J.

AU - Onland-Moret, N. Charlotte

AU - Poulter, Neil

AU - Psaty, Bruce

AU - Redline, Susan

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Schunkert, Heribert

AU - Sever, Peter

AU - Shuldiner, Alan R.

AU - Silverstein, Roy L.

AU - Stanton, Alice

AU - Thorand, Barbara

AU - Trip, Mieke D.

AU - Tsai, Michael Y.

AU - Van Der Harst, Pim

AU - Van Der Schoot, Ellen

AU - Van Der Schouw, Yvonne T.

AU - Verschuren, W. M.Monique

AU - Watkins, Hugh

AU - Wilde, Arthur A.M.

AU - Wolffenbuttel, Bruce H.R.

AU - Whitfield, John B.

AU - Hovingh, G. Kees

AU - Ballantyne, Christie M.

AU - Wijmenga, Cisca

AU - Reilly, Muredach P.

AU - Martin, Nicholas G.

AU - Wilson, James G.

AU - Rader, Daniel J.

AU - Samani, Nilesh J.

AU - Reiner, Alex P.

AU - Hegele, Robert A.

AU - Kastelein, John J.P.

AU - Hingorani, Aroon D.

AU - Talmud, Philippa J.

AU - Hakonarson, Hakon

AU - Elbers, Clara C.

AU - Keating, Brendan J.

AU - Drenos, Fotios

PY - 2012/11/2

Y1 - 2012/11/2

N2 - Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

AB - Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

UR - http://www.scopus.com/inward/record.url?scp=84868470681&partnerID=8YFLogxK

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U2 - 10.1016/j.ajhg.2012.08.032

DO - 10.1016/j.ajhg.2012.08.032

M3 - Article

C2 - 23063622

AN - SCOPUS:84868470681

SN - 0002-9297

VL - 91

SP - 823

EP - 838

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

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